While there are several note-worthy differences between males and females with regard to smoking behavior, ultimately none are as worrisome as the disparity in ability to quit smoking. Although multiple explanations for why women are less successful in their abstinence attempts have been proffered, the observation that women are more likely to experience emergence of depressive symptoms during smoking cessation, a known risk factor for relapse, may be a critical contributor to this sex-specific recidivism. Several lines of evidence suggest that nicotine modulation of gamma-aminobutyric acid (GABA) may play an important role in this interplay between sex, depression and smoking recidivism. Using proton magnetic resonance spectroscopy (1H-MRS), our group has found reductions in occipital cortex GABA concentrations in subjects with unipolar depression and premenstrual dysphoric disorder. Recently, we have published pilot data from healthy smoking men and women indicating that nicotine induced alterations in cortical GABA levels are found solely in women and are characterized by reduced GABA levels in the follicular phase and abolished menstrual cyclicity in GABA levels. Reductions in cortical GABA levels in women who smoke may therefore render them at increased risk for depression, which sabotages their attempts to quit. Thus, we propose to employ 1H-MRS to measure GABA levels in the occipital cortex of a larger group of healthy smoking and nonsmoking women and men to confirm the impact of sex as well as menstrual cycle phase on nicotine-induced alterations in cortical GABA concentrations. In addition, women will be invited to undergo 10-14 days of abstinence using contingency management so that we may examine the relationship between baseline GABA and changes in GABA with abstinence and emergence of negative affect and craving. This project is both novel and timely as it responds directly to the mandate from NIDA to examine the impact of sex-specific factors on substance abuse/dependence disorders in order to enhance long-term abstinence. RELEVANCE TO PUBLIC HEALTH: The study outlined in this proposal will not only further our knowledge regarding the influence of nicotine on brain chemistry, it may also lead to new medications to enhance smoking cessation in females and/or others at risk for depression during smoking abstinence. [unreadable] [unreadable]